Granzyme B mediates neurotoxicity through a G‐protein‐coupled receptor
- 24 April 2006
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 20 (8) , 1209-1211
- https://doi.org/10.1096/fj.05-5022fje
Abstract
Neuroinflammatory diseases such as multiple sclerosis (MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Giα protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be...Keywords
Funding Information
- National Institutes of Health (P01MH070056, R01NS039253, R01NS043990)
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